JP2018518501A - Combination therapy of myocardial myosin activator and sinoatrial node If current inhibitor - Google Patents

Abstract

Disclosed herein is a combination therapy for the treatment of heart failure using a myocardial myosin activator such as omecamtivecarbyl and a sinoatrial node If current inhibitor such as ivabradine. Also disclosed herein are compositions comprising a myocardial myosin activator and a sinoatrial node If current inhibitor. [Selection figure] None

Description

  A combination therapy of a myocardial myosin activator and a sinoatrial node If current inhibitor and a pharmaceutical composition thereof are provided.

  Heart failure (HF) is a chronic disease characterized by systolic disorders that lead to reduced systemic organ blood perfusion that ultimately decouples oxygen consumption and transport to tissues, and ultimately death. Circulation mechanisms of blood circulation and metabolism are effective in the short term, but can be harmful in the long term. Pharmacological treatment of HF is based on partially obstructing the compensatory mechanism and improving myocardial contractility. Despite the best available pharmacological treatments for heart failure, such as ACE-I / ARB, beta blockers, and aldosterone antagonists, morbidity and mortality remain high, with approximately 30% of patients diagnosed Hospitalized with heart failure within 3 months of life and survival rate of 50% (enter reference and update statistics based on AHA / ACC HF guidelines).

  A compensatory increase in resting heart rate is considered a modifiable risk factor for patients with HF. Beta blockers have been particularly successful in reducing heart rate, among other measures, and have improved HF morbidity and mortality. However, a significant proportion of patients cannot tolerate the negative inotropic or relaxant effects of beta-blockers and maintain high heart rate even under the maximum tolerated doses of these drugs. Ivabradine is an If current-specific inhibitor of the sinoatrial node that causes a reduction in heart rate, which leads to an associated increase in the diastole of the cardiac cycle and coronary filling without changes in myocardial contractility or relaxation Can do. The efficacy and safety of ivabradine in reducing HF morbidity and mortality is an additional treatment for patients with maximum resting background treatment and sustained high resting heart rate (greater than 70-75 bpm) Proven. However, the use of ivabradine can cause symptomatic bradycardia if the heart rate drop exceeds the ability of compensatory physiological mechanisms to maintain sufficient blood pressure.

  Myocardial contractility is another target for HF treatment. Myocardial myosin activators, such as omecamtiv mecarbil, are a class of new mechanisms designed specifically to improve myocardial contractility. The mechanism of action of the myosin activator increases the number of active myosin-actin interactions, resulting in prolonged systolic ejection time, but does not increase the rate of contraction and does not significantly increase oxygen consumption. Promotes increased stroke volume. The availability of oral formulations for continuous use, lack of arrhythmia, and increased myocardial oxygen consumption make omecamtivmecarbyl a promising therapeutic option for HF. Extending systolic ejection time without simultaneous extension of diastolic time can reduce the time available for coronary artery filling.

  Thus, HF remains in a state of special unmet need that would benefit from the development of additional treatment options to improve cardiac contractility while maintaining coronary flow during diastole. . The combination of ivabradine and omecamtivmecarvir provides an opportunity for the additive utility of reducing heart rate and improving myocardial contractility in heart failure each obtained from individual treatments. In addition, symptomatic bradycardia that can be attributed to ivabradine may be offset by the improvement in myocardial contractility seen with omecamib mecarvir, and diastolic coronary filling that may be attributed to omecamib mecarvir There is an opportunity for mitigating mutual risk, as the decline in can be offset by an increase in diastolic coronary filling that may be due to ivabradine.

  Provided herein is a method of treating a subject with heart failure, comprising administering to the subject a myocardial myosin activator and a sinoatrial node If current inhibitor. In various cases, the subject suffers from one or more of congestive heart failure, systolic heart failure, and heart failure with reduced left ventricular ejection fraction. The methods provided herein can result in a reduction in ischemic events as compared to administration of a cardiac myosin activator (eg, omecamtibmecarbyl) alone. The methods provided herein can result in a reduced systolic to diastolic ratio as compared to administration of a myocardial myosin activator (eg, omecamtibmecarbyl) alone. The methods provided herein can result in a decrease in troponin levels as compared to administration of a cardiac myosin activator (eg, omecamtibmecarbyl) alone. The methods provided herein can provide improved cardiac contractility as compared to administration of a myocardial myosin activator (eg, omecamtibmecarbyl) alone.

  In various cases, the myocardial myosin activator is omecamcibmecarbyl, or a pharmaceutically acceptable salt or hydrate thereof. In various cases, the sinoatrial node If current inhibitor is ivabradine, or a pharmaceutically acceptable salt or hydrate thereof. In some cases, omecamib mecarvir and ivabradine are administered sequentially (eg, omecamib prior to ivabradine or omecamtiv after ivabradine). In other cases, omecamtivmecarvir and ivabradine are administered simultaneously. Omecamtivecalvir and ivabradine can be prescribed simultaneously.

  In the methods provided herein, the omecamtivmecarvir and ivabradine can be administered orally, intravenously, subcutaneously, intramuscularly, intrathecally, or via inhalation. In various cases, the omecamcibmecarbyl is administered orally. In various cases, the ivabradine is administered orally. In some cases, the omecamtivmecarvir and ivabradine are each administered orally.

  In the methods disclosed herein, the omecamcibmecarbyl can be administered in a total daily dose of 10 mg to 200 mg.

  In the methods disclosed herein, the ivabradine can be administered in a total daily dose of 2.5 mg to 20 mg.

  Further provided herein is a pharmaceutical composition comprising a myocardial myosin activator and a sinoatrial node If current inhibitor. In various cases, the composition may be in the form of a tablet.

  In various cases, the myocardial myosin activator is omecamcibmecarbyl, or a pharmaceutically acceptable salt or hydrate thereof. In some cases, the omecamib mecarvir dihydrochloride hydrate exists.

  In various cases, the sinoatrial node If current inhibitor is ivabradine, or a pharmaceutically acceptable salt or hydrate thereof. In some cases, the ivabradine is present as ivabradine hydrochloride.

  In various cases, the composition can further include a controlled release agent; a pH adjusting agent; a filler; and a lubricant. In some cases, the controlled release agent comprises methylcellulose, hydroxypropylmethylcellulose, or a combination thereof. In some cases, the controlled release agent comprises methylcellulose and hydroxypropylmethylcellulose. In various cases, the pH adjusting agent comprises fumaric acid, maleic acid, glutamic acid, tartaric acid, or combinations thereof. In some cases, the pH adjuster comprises fumaric acid. In various cases, the filler comprises microcrystalline cellulose, lactose monohydrate, or a combination thereof. In various cases, the lubricant comprises magnesium stearate.

  Further provided herein is omecamib mecarvir or a pharmaceutically acceptable salt or hydrate thereof for use in combination with ivabradine or a pharmaceutically acceptable salt or hydrate thereof for the treatment of heart failure. To provide.

  Further provided herein is ivabradine or a pharmaceutically acceptable salt or hydrate thereof for use in combination with omecamtivmecarvir or a pharmaceutically acceptable salt or hydrate thereof for the treatment of heart failure. To provide.

  Furthermore, for oral administration comprising ivabradine, or a pharmaceutically acceptable salt or hydrate thereof, and omecamtivemecarbyl, or a pharmaceutically acceptable salt or hydrate thereof, as independent entities Concomitant therapeutic agents are provided herein. In some cases, the combination therapy is for the treatment of heart failure.

Vehicle (VEH) in wake telemetry beagle dogs in a repeat therapy setting with either ivabradine (IVA, 5 mg / kg orally twice a day for at least 5 days) or placebo (CTRL, sterile water for at least 5 days) Or left ventricular systolic ejection time (SET), mechanical systolic to diastolic ratio (S / D) measured prior to and during acute intravenous administration of either omecamcibmecarbyl (OM) ) And changes in heart rate (HR). Vehicle (VEH) in wake telemetry beagle dogs in a repeat therapy setting with either ivabradine (IVA, 5 mg / kg orally twice a day for at least 5 days) or placebo (CTRL, sterile water for at least 5 days) Or between both systolic (dP / dt _max ) and diastolic (dP / dt _min ) measured before and during acute intravenous administration of either omecamcibmecarbyl (OM) The peak of the left ventricular pressure change rate and the change of the expansion time constant (Tau) are shown.

  A combination therapy of a myocardial myosin activator and a sinoatrial node If current inhibitor is provided. In various cases, the structure:

Omecamtibmecarbyl (AMG 423, CK-1824752), i.e. methyl 4- (2-fluoro-3- (3- (6-methylpyridin-3-yl) ureido) benzyl) piperazine-1-carboxyl Rate, or a pharmaceutically acceptable salt or hydrate thereof, and structure:

Ivabradine having the following: 3- {3-[{[(7S) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl] methyl} (methyl) Amino] propyl} -7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one, or a pharmaceutically acceptable salt or hydrate combination therapy thereof Provide in the letter. As used throughout, references herein to omecamtivmecarbyl include pharmaceutically acceptable salts or hydrates thereof, unless otherwise specified. Similarly, references herein to ivabradine include its pharmaceutically acceptable salts or hydrates unless otherwise specified.

  Omecamtivamecarbyl is a direct activator of cardiac myosin, a motor protein that causes cardiac contraction. This is potentially useful as a treatment for heart failure in both intravenous and oral formulations. The preparation and therapeutic use of omecamtivmecarvir and its pharmaceutically acceptable salts is described in WO 2006/009726.

  Ivabradine is a specific inhibitor of the sinoatrial node If current that reduces heart rate without impaired myocardial contractility. The efficacy and safety of ivabradine in reducing HF morbidity and mortality is an additional treatment for patients with maximum resting background treatment and sustained high resting heart rate (greater than 70-75 bpm) Proven.

  A sinoatrial node If current inhibitor, more specifically ivabradine and its hydrates and salts with pharmaceutically acceptable acids, more specifically its hydrochloride, is an attractive drug that causes heart rate reduction Has physical and therapeutic properties. Lower heart rates are associated with decreased outcome of heart failure (Kjekshus J, Gullestad L. Eur Heart J. 1999; 1 (suppl H): H64-H69; McAlister FA, et al. Ann Intern Med. 2009; 150: 784-794), so these compounds may be useful in the management of heart failure (reference shift). It may also provide additional utility in the treatment of angina or certain supraventricular rhythm disorders.

  Preparation and therapeutic use of ivabradine and its salts with pharmaceutically acceptable acids, more specifically its hydrochloride salt, is described in European Patent Specification EP 0 534 859.

  Described herein is the discovery that sinoatrial node If current inhibitors, such as ivabradine, can enhance the effects of myocardial myosin activators, such as omecamcibmecarvir. Thus, the improvement in this effect is related to the synergistic action between the active ingredient, the sinoatrial node If current inhibitor and the myocardial myosin activator.

Heart failure Methods and compositions for the treatment of heart failure are provided herein. Contemplated conditions include, but are not limited to, diseases associated with acute (or decompensated) congestive heart failure, chronic congestive heart failure, and systolic heart dysfunction.

  “Treatment” or “treating” means any treatment of a disease in a patient, a) preventing the disease, ie, not developing clinical symptoms of the disease; b) inhibiting the disease C) slowing or suppressing the onset of clinical symptoms; and / or d) alleviating the disease, i.e., causing regression of clinical symptoms. The treatment of the diseases and disorders herein also includes a pharmaceutical formulation as described herein for a subject (ie, an animal, preferably a mammal, most preferably a human), eg, chronic heart failure, that may be in need of prophylactic treatment. Is intended to include prophylactic administration.

  The term “therapeutically effective amount” means an amount effective when administered to a human or non-human patient to treat a disease, eg, a therapeutically effective amount refers to a disease or disorder that responds to myosin activation. It can be in an amount sufficient to treat. The therapeutically effective amount can be ascertained experimentally, for example, by assaying the blood concentration of the chemical, or theoretically by calculating bioavailability.

  The methods and compositions provided herein can result in a reduced incidence of ischemic events as compared to treatment of heart failure with omecamtivmecarvir alone. In some cases, the methods and compositions provided herein can reduce the systolic to diastolic ratio as compared to treatment of heart failure with omecamtivmecarvir alone. In some cases, the methods and compositions provided herein can result in a decrease in troponin levels compared to treatment of heart failure with omecamtivmecarvir alone.

Pharmaceutical compositions and dosing Omecamtibmecarbyl, or a pharmaceutically acceptable salt or hydrate thereof, and ivabradine, or a pharmaceutically acceptable salt or hydrate thereof, for use in the treatment of heart failure Therapies are provided herein. The two active ingredients can be administered sequentially or in parallel. In parallel, the active agents can be administered separately or formulated simultaneously.

“Pharmaceutically acceptable salts” include salts with inorganic acids, such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, etc .; and Salts with organic acids such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2 - hydroxyethyl sulfonate, benzoate, salicylate, stearate, and alkanoate such as acetate, HOOC- _{(CH 2) (wherein,} n is 0 to 4) n -COOH, such as However, it is not limited to these. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium. One skilled in the art will recognize a variety of synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable salts.

  The dosage of the active substance (or active substances) can vary depending on the nature and severity of the disorder, the route of administration, and the age and weight of the patient. In the compositions provided herein, the dosage is one or more administrations per 24 hours, with a myocardial myosin activator, such as omecamtivmecarvir or a pharmaceutically acceptable salt or hydration thereof. Products, such as omecamtivemecarbyl dihydrochloride hydrate, ranging from 10 mg to 200 mg (eg, based on the weight of the free base activator), and a sinoatrial node If current inhibitor, such as ivabradine or The pharmaceutically acceptable salt or hydrate ranges from 2.5 to 30 mg (eg, based on the weight of the free base inhibitor). In some cases, the sinoatrial node If current inhibitor is ivabradine or a pharmaceutically acceptable salt or hydrate thereof, and the dosage of ivabradine or a pharmaceutically acceptable salt or hydrate thereof is Once or twice daily, the total amount per day is 2.5-20 mg or 5 mg-15 mg, or 10-15 mg (eg, based on the weight of the free base ivabradine). In various cases, the myocardial myosin activator is omecamcibmecarbyl or a pharmaceutically acceptable salt or hydrate thereof, and the daily dose is once or twice daily, 12.5 mg to 150 mg, 12.5 mg to 100 mg, 12.5 mg to 75 mg, 25 mg to 75 mg, 12.5 mg to 50 mg, or 25 mg to 50 mg (for example, based on the weight of the free base omecamibmecarbyl) is there.

  In some cases, the formulation is capable of controlled release of omecamtibmecarbyl or a pharmaceutically acceptable salt or hydrate thereof, optionally further ivabradine or a pharmaceutically acceptable salt or Tablet formulation containing hydrate. The pharmaceutical formulations described herein are uniformly omecamib mecarbyl at a pace controlled by the diffusion of omecamcibmecarbyl through the gel layer formed by hydration of the controlled release agent in the tablet. Can be released. In some embodiments in conjunction with other embodiments described above or below, the modified release matrix tablets of the present invention exhibit minimal pH dependent release in vitro. In some embodiments, in conjunction with other embodiments described above or below, complete release of omecamtivmecarbyl is achieved within 24 hours with both pH 2 and 6.8 elution solvents, and between subjects and subjects. Variability as well as food effects can be reduced. It has been found that the modified release matrix tablet dosage form of the present invention is superior to the previous immediate release dosage form in minimizing the peak-to-trough ratio of plasma. As a result, the modified release matrix tablets of the present invention reduce plasma concentration fluctuations, reduce side effects, and improve safety and efficacy. The modified release matrix tablets of the present invention are also expected to improve patient compliance by reducing dosing frequency. Furthermore, the modified release matrix tablets of the present invention are physicochemically stable and do not cause changes in physical attributes, assays, impurities, or dissolution profiles after storage for 6 months at 40 ° C./75% relative humidity. A tablet formulation for controlled release of omecamtivecarbyl is described in WO 14/152236.

  In some embodiments, in conjunction with other embodiments described above or below, omecamibmecarvir exposure in humans from 2 to 12 hours after administration is 50 to 800 ng / ml.

  In some embodiments, in conjunction with other embodiments described above or below, omecamcibmecarvir exposure in humans up to 2-12 hours after administration remains at 100-800 ng / ml.

  In some embodiments, in conjunction with other embodiments described above or below, omecamcibmecarbyl is released at the following intervals: 30% or less of the dosage dissolves in 1 hour; 30-75 in 3 hours % Dose is dissolved; and over 12% dose is dissolved in 12 hours.

  In some embodiments, in conjunction with other embodiments described above or below, omecamcibmecarbyl is released at the following intervals: 30% or less of the dose dissolves in 2 hours; 30-75 in 6 hours % Of the dose is dissolved; and over 16% of the dose is dissolved in 16 hours.

  Omecamibmecarbyl, or a pharmaceutically acceptable salt or hydrate thereof; ivabradine, or a pharmaceutically acceptable salt or hydrate thereof; a controlled release agent; a pH regulator; a filler; A pharmaceutical formulation comprising an agent is provided.

  Controlled release agent: As used herein, the term “controlled release agent” refers to an agent that facilitates the release of an active ingredient from the composition in a controlled manner. In some embodiments in conjunction with other embodiments described above or below, the controlled release agent forms a gel upon hydration. Controlled release agents include pullulan, dextrin, sodium and calcium acids, polyacrylic acid, polymethacrylic acid, polymethyl vinyl ether-co-maleic anhydride, polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, Hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethyl methacrylate, sodium carboxymethylcellulose, carboxymethylcellulose calcium, methylcellulose, maltodextrin, xanthan gum, tragacanth gum, agar, gellan gum, kayara gum, alginic acid, pectin, pregelatinized starch, polyvinyl alcohol, Carboxymethyl ethyl cellulose Cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl alcohol phthalate, polyvinyl butyrate phthalate, polyvinyl butyrate phthalate , Vinyl acetate / maleic anhydride copolymer, styrene / maleic acid monoester copolymer, methyl acrylate / methacrylic acid copolymer, styrene / acrylic acid copolymer, methyl acrylate / methacrylic acid / octyl acrylate Methacrylic acid / methyl methacrylate copolymer, benzylaminomethylcellulose, diethylaminomethylcellulose, piperidylethylhydroxyethylcellulose, cellulose acetate dimethylaminoacetate, vinyldiethylamine / vinyl acetate copolymer, vinylbenzylamine / vinyl acetate copolymer, polyvinylacetal diethylaminoacetate, vinylpiperidyl Acetoacetal / vinyl acetate copolymer, polydiethylaminomethylstyrene, methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer and polydimethylaminoethyl methacrylate, 2-methyl-5-vinylpyridine / methyl methacrylate / methacrylic acid copolymer , 2-Methyl-5-vinylpyridine / Ac Methyl lurate / methacrylic acid copolymer, 2-vinyl-5-ethylpyridine / methacrylic acid / methyl acrylate copolymer, 2-vinylpyridine / methacrylic acid / acrylonitrile copolymer, carboxymethylpiperidyl starch, carboxymethylbenzylaminocellulose, N-vinyl Glycine / styrene copolymer, chitosan, poly (vinyl alcohol), anhydrous maleic copolymer, poly (vinyl pyrrolidone), starch and starch-based polymer, poly (2-ethyl-2-oxazoline) (poly (2-ethyl-2-oxazoline)) ), Poly (ethyleneimine), polyurethane hydrogel, welan gum, rhamzan gum, polyvinyl acetate, ethyl cellulose, Eudragit RL, RS, NE 30D, Kollicoat EM 30D, or combinations thereof.

  In some embodiments in conjunction with other embodiments described above or below, the controlled release agent is a polymer.

  In some embodiments in conjunction with other embodiments described above or below, the controlled release agent comprises pullulan, dextrin, sodium and calcium acids, polyacrylic acid, polymethacrylic acid, polymethylvinylether-co-maleic anhydride. Acid, polyvinylpyrrolidone, polyethylene oxide, polyethylene glycol, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethyl methacrylate, sodium carboxymethylcellulose, carboxymethylcellulose calcium, methylcellulose, maltodextrin, xanthan gum, tragacanth gum, agar, gellan gum, cayara gum ( kayara gum), alginic acid, pectin, pregelatinized starch, polyvinyl alcohol Carboxymethyl ethyl cellulose, cellulose acetate phthalate, cellulose acetate succinate, methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl alcohol phthalate, polyvinyl butyrate Rate phthalate, polyvinyl acetal phthalate, vinyl acetate / maleic anhydride copolymer, styrene / maleic acid monoester copolymer, methyl acrylate / methacrylic acid copolymer, styrene / acrylic acid copolymer, methyl acrylate Methacrylic acid / octyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, benzylaminomethylcellulose, diethylaminomethylcellulose, piperidylethylhydroxyethylcellulose, cellulose acetate dimethylaminoacetate, vinyldiethylamine / vinyl acetate copolymer, vinylbenzylamine / vinyl acetate copolymer, polyvinyl Acetal diethylaminoacetate, vinyl piperidyl acetoacetal / vinyl acetate copolymer, polydiethylaminomethylstyrene, methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer and polydimethylaminoethyl methacrylate, 2-methyl-5 vinylpyridine / methacrylic acid Methyl / methacrylic acid copolymer, -Methyl-5-vinylpyridine / methyl acrylate / methacrylic acid copolymer, 2-vinyl-5-ethylpyridine / methacrylic acid / methyl acrylate copolymer, 2-vinylpyridine / methacrylic acid / acrylonitrile copolymer, carboxymethylpiperidyl starch, carboxy Methylbenzylaminocellulose, N-vinylglycine / styrene copolymer, chitosan, poly (vinyl alcohol), anhydrous maleic copolymer, poly (vinyl pyrrolidone), starch and starch-based polymers, poly (2-ethyl-2-oxazoline) (poly ( 2-ethyl-2-oxazole)), poly (ethyleneimine), polyurethane hydrogel, welan gum, rhamzan gum, polyvinyl acetate, ethyl cellulose, Eudragit RL, Selected from RS, NE 30D, and Kollicoat EMM 30D, or any combination thereof. In various cases, the controlled release agent comprises methylcellulose, hydroxypropylmethylcellulose, or a combination thereof. Examples of contemplated methylcellulose and hydroxypropylmethylcellulose include METHOCEL K100 MPrem CR, METHOCELL K100 LV Prem CR, and mixtures thereof. METHOCELL K100 MPrem CR is a hypromellose having a viscosity of 100,000 mPa / s at 2% concentration in water at 20 ° C., and METHOCELL K100 LV Prem CR is a hypromellose having a viscosity of 100 mPa / s at 2% concentration in water at 20 ° C. It is.

  pH adjuster: As used herein, the term “pH adjuster” refers to an agent that can adjust pH to a desired range. In some embodiments in conjunction with other embodiments described above or below, the pH adjusting agent is an acidifying agent. In some embodiments in conjunction with other embodiments described above or below, the pH adjusting agent is included in an amount sufficient to lower the pH. Examples of pH adjusters include maleic acid, citric acid, tartaric acid, pamoic acid, fumaric acid, salicylic acid, 2,6-diaminohexanoic acid, camphorsulfonic acid, glycerophosphoric acid, 2-hydroxyethanesulfonic acid, isethionic acid, succinic acid, Carbonic acid, p-toluenesulfonic acid, aspartic acid, 8-chlorotheophylline, benzenesulfonic acid, malic acid, orotic acid, oxalic acid, benzoic acid, 2-naphthalenesulfonic acid, stearic acid, adipic acid, p- Aminosalicylic acid, 5-aminoslicylic acid, ascorbic acid, sulfuric acid, cyclamic acid, sodium lauryl sulfate, glucoheptonic acid, glucuronic acid, glycine, sulfuric acid, mandelic acid, 1,5-naphthalenedisulfone Acid, nicotinic acid, oleic acid, 2-oxoglutaric acid, pyridoxal-5-phosphate, undecanoic acid, p-acetamidobenzoic acid, o-acetamidobenzoic acid, m-acetamidobenzoic acid, N-acetyl-L-aspartic acid, Camphoric acid, dehydrocholic acid, malonic acid, edetic acid, ethylenediaine tetraacetic acid, ethyl sulfate, hydroxyphenylbenzoylbenzoic acid, glutamic acid, glycyrrhizic acid, 4-hexylresorcinol, hippuric acid, p-phenolsulfonic acid 4-hydroxybenzoic acid, 3-hydroxybenzoic acid, 3-hydroxy-2-naphthoic acid, 1-hydroxy-2naphthoic acid, lactobionic acid, 3'-adenylic acid, 5'-adenylic acid, mucinic acid, galactaric acid Pantothenic acid, pectinic acid, polygalacturonic acid, 5-sulfosalicylic acid, 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-propanesulfonic acid, terephthalic acid, 1-hydroxy-2 -Naphthoic acid, as well as combinations thereof. In some embodiments in conjunction with other embodiments described above or below, the pH adjuster includes, for example, maleic acid, citric acid, malic acid, fumaric acid, sulfuric acid, tartaric acid, lactic acid, salicylic acid, aspartic acid, amino Salicylic acid, malonic acid, glutamic acid, and combinations thereof.

  In some embodiments in conjunction with other embodiments described above or below, the pH modifier is maleic acid, citric acid, malic acid, fumaric acid, sulfuric acid, tartaric acid, lactic acid, salicylic acid, aspartic acid, aminosalicylic acid, Selected from malonic acid, glutamic acid, and any combination thereof.

  In some embodiments in conjunction with other embodiments described above or below, fumaric acid was used as the pH modifier, which is less hygroscopic than citric acid and High compatibility with hydrochloride hydrate, there is almost no change in active form when stored at 40 ° C / 75% relative humidity for 6 months, and there is no change in the appearance of the tablet, leading to improved quality of the final product Because. Furthermore, fumaric acid is more acidic (2 times) than citric acid. Thus, in order to adjust the pH of the microenvironment and improve the release of omecamcibmecarbyl in a neutral environment, fumaric acid is used in a weight ratio of 1: 1 instead of 2: 1 to the active substance. It is more efficient to use. Fumaric acid also has a very slow dissolution rate. As a result, fumaric acid stays longer in the tablet and better maintains the low microenvironmental pH, resulting in a more complete release of omecamcibmecarbyl within 24 hours. In some embodiments, as a result, the pH modifier is selected from maleic acid, fumaric acid, tartaric acid, glutamic acid, and any combination thereof. In some embodiments, the pH adjuster comprises fumaric acid.

  Filler: As used herein, the term “filler” refers to a component of a pharmaceutical composition to achieve a desired weight, for example, to increase the bulk weight of the material to be tableted. Refers to one or more substances that can be added. Fillers include, but are not limited to, starch, lactose, mannitol (eg, Pearlitol ™ SD 200), cellulose derivatives, calcium phosphate, sugars, and the like.

  Different grades of lactose include lactose monohydrate, lactose DT (direct compression), lactose anhydride, Flowlac (TM) (available from Meggle products), Pharmatose (TM) (available from DMV), etc. However, it is not limited to these. Different grades of starch include corn starch, potato starch, rice starch, wheat starch, pregelatinized starch (commercially available as PCS PC10 from Signet Chemical Corporation), and Colorcon Star 1500, Star 1500 LM grade (low water content grade). ), Fully pregelatinized starch (commercially available from Essex Grain Products as National 78-1551), and the like. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include, but are not limited to, CEOLUS ™ KG801, Avicel ™ PH101, PH102, PH301, PH302, and PH-F20, microcrystalline cellulose 114, and microcrystalline cellulose 112. Not. Other useful fillers include, but are not limited to, carmellose, sugar alcohols such as mannitol, sorbitol, and xylitol, calcium carbonate, magnesium carbonate, dicalcium phosphate, and tricalcium phosphate.

  In some embodiments in conjunction with other embodiments described above or below, the filler is selected from starch, lactose, mannitol (eg, Pearlitol ™ SD 200), cellulose derivatives, calcium phosphate, and sugar. .

  In some embodiments in conjunction with other embodiments described above or below, the filler is anhydrous lactose or lactose monohydrate. In some embodiments in conjunction with other embodiments described above or below, the filler is lactose DT, Flowlac ™, or Pharmatose ™.

  In some embodiments in conjunction with other embodiments described above or below, the filler may be corn starch, potato starch, rice starch, wheat starch, pregelatinized starch (eg, Starch 1500 or Starch 1500 LM grade (low Water grade)), or fully pregelatinized starch.

  In some embodiments in conjunction with other embodiments described above or below, the filler is a microcrystalline cellulose, such as CEOLUS ™ KG801, Avicel ™ PH101, PH102, PH301, PH302, and PH. -F20, microcrystalline cellulose 114, or microcrystalline cellulose 112.

  In some embodiments in conjunction with other embodiments described above or below, the filler is carmellose, mannitol, sorbitol, xylitol, calcium carbonate, magnesium carbonate, dicalcium phosphate, or tricalcium phosphate.

  Lubricant: As used herein, the term “lubricant” is added to the components of the composition to reduce sticking by the solid agent to the device used to manufacture the unit dosage form. Refers to one or more substances that can be made. Lubricants include stearic acid, hydrogenated vegetable oil, hydrogenated soybean oil and hydrogenated soybean oil and castor wax, stearyl alcohol, leucine, polyethylene glycol, magnesium stearate, glyceryl monostearate, stearic acid, glyceryl behenate, Examples include polyethylene glycol, ethylene oxide polymer, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, and mixtures thereof.

  In some embodiments in conjunction with other embodiments described above or below, the lubricant is stearic acid, hydrogenated vegetable oil, hydrogenated soybean oil, hydrogenated soybean oil, castor wax, stearyl alcohol, leucine, polyethylene. Glycol, magnesium stearate, glyceryl monostearate, stearic acid, glyceryl behenate, polyethylene glycol, ethylene oxide polymer, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, or Any mixture thereof.

  As will be appreciated, the steps of the methods provided herein need not be performed any particular number of times or in any particular order. Further objects, advantages, and novel features of the invention (s) will become apparent to those skilled in the art upon consideration of the following examples, which are intended to be illustrative and not limiting. Not intended.

Example 1
Evaluation of omecamchibmecarbyl in high and low heart rate anesthetized dogs: beagle dogs (male; 10-12 kg), morphine (1-2 mg / kg intramuscularly) and alpha-chloralose (80-120 mg / kg intravenously) Induced to anesthesia by treatment with solution strength: 10 mg / ml). Immediately after induction, anesthesia is maintained for the duration of the test by constant alpha-chloralose infusion (intravenous 35-75 mg / kg / hour) (feeding is controlled with an intravenous pump). Dogs are intubated with an endotracheal tube and immediately ventilated with room air by positive pressure breathing (Harvar Large Animal pump; rate: 15 strokes / min; volume: 100-150 ml / stroke) and assessed by arterial blood gas measurements. A thermostatically controlled heating blanket is used to maintain normal core body temperature (37 ° C.). Intravenous infusion (saline: 2-5 ml / kg / hour) is infused throughout the procedure and a Foley catheter is placed in the bladder to ensure urine flow.

  Cardiovascular instruments: Make bilateral incisions in the neck and groin and use conventional vasotomy methods to place fluid-filled catheters in the external jugular vein (one or both sides), carotid artery (one side right or left), and femur Insert into arteries and veins (one or both sides). Arterial pressure is recorded from the femoral artery and left ventricular pressure is recorded from a solid state catheter (Millar) inserted through the carotid or femoral artery. The jugular vein cannula is used for blood collection (measuring drug levels) and the femoral vein is used for injection of the test substance. Vascular cannula patency is maintained with heparinized saline (50 units / ml). ECG (lead II and chest) is recorded from the hypodermic needle electrode. All tube signals are collected with a computerized data acquisition system (EMKA iox) and analyzed after testing (EMKA ECGAAuto). Ultrasound echocardiography (GE Vivid S6, phased array probe; 3.5-8 MHz) images were collected from right parasternal and tip radiographs.

  Drug infusion: After use of the surgical instrument, the dog is stabilized (20-30 minutes) to establish baseline values for all cardiovascular parameters. The test article was administered through an indwelling venous catheter for 30 minutes at a constant infusion rate and volume using a syringe pump. Each dog was treated with vehicle and 6 doses of omecamib mecarvir (see table).

  Heart rate pacing: High maintained by cardiac pacemakers inserted into the two groups of dogs, the first group of low heart rate values (50-60 bpm) and the right ventricle (via the jugular vein) Administer to heart rate (about 120 bpm) second group: In each group, the ejection fraction (or shortening rate) induced by omecamcibmecarbyl and changes in systolic and diastolic time intervals are compared in high and low heart rate dogs. Low heart rate dogs mimic treatment with ivabradine.

  Plasma drug levels: Blood samples (1-2 mL) are collected at baseline (pre-infusion) and at each omecamcibmecarbyl infusion period (eg, 10 min, 20 min, and 29 min time points) to determine drug levels Measure. Blood samples are collected in tubes treated with anticoagulant (EDTA) and then kept on ice, followed by centrifugation to obtain plasma. The plasma sample is then frozen and transferred to bioanalysis.

Example 2
This study included a healthy male Beagle dog (n = 7) equipped with a continuous monopolar electrocardiogram (ECG) and a wireless telemetry device providing whole body (artery, AoP) and left ventricular (LVP) pressure signals. Using. After acclimatization of the sling, these animals were either cross-designed with ivabradine (IVA, twice daily at 5 mg / kg) administered at a dose of 10 mL / kg or a placebo control (sterile water) , CTRL) were assigned to receive repeated oral (by gavage) treatment for 5 days.

  Animals are restrained in a sling and subjected to acute intravenous administration of either sterile water (VEH, 4th and 11th day of administration) or omecamtivmecarvir (OM, 5th and 12th day of administration). did. OM treatment is a dose escalation design targeting a plasma concentration of 600 and 1000 ng / mL for a cumulative dose of 5.293 mg / kg (90 minutes each over 30 minutes loading infusion followed by 60 minutes maintenance infusion) ) Over a 3 hour infusion period (shown in Table A below). Intravenous vehicle treatment was time and volume matched.

Telemetry data was collected continuously before and during dosing for at least 90 minutes and for at least 20 hours after dosing. LVP and ECG signals were digitized with a sampling rate of at least 1000 Hz. The data is from a heart rate (HR) and a pressure waveform that includes mean systolic (MSP) and end-diastolic (full, EDP) pressure, systolic / diastolic pressure change peak (dP / dt _{max / min} ). The resulting left ventricular hemodynamic / mechanical indicators were analyzed for diastolic time constant (tau) and contraction index (CI; dP / dt _max normalized by pressure at dP / dt _max ). These data also include systolic and dilated, including estimated duration of systolic ejection (SET), contraction (CT), active relaxation (RT), and full interval (FT) obtained from left ventricular pressure waveform The interval between phases and the ratio of systolic to diastolic interval (S / D: SET / RT + FT) were also analyzed.

  These left ventricular indices were evaluated only before and during IV treatment with OM or vehicle in sling restrained animals. Cardiovascular responses at each dose level were observed for up to 90 minutes, ie for a total of 3 hours (4, 5, 11, and 12 days in the dose administration paradigm during VEH and OM IV administration). Overall, intra-sling cardiovascular data is reported at the following predetermined / target time points: pre-dose (ie, baseline, before) and near the end of each infusion period (ie, up to 4 Time points, D1-D4). The signal is continuously analyzed over a 5 minute epoch, and the pre-dose (ie, pre-) values represent the overall average over at least 5 epochs (ie, 25 minutes) taken just before the start of dosing, and values during dosing Reflects the 5 minute average (ie, 1 epoch) taken before the end of (estimated) each injection. Both data are shown as mean and standard deviation in the table / figure summary; the plot between beats against heart rate is part of the test file.

  Table 1 shows the effect of repeated treatment with ivabradine (IVA, 5 mg / kg twice a day for at least 5 days) on left ventricular hemodynamics, as well as baseline measured in the preparation of awake sling restraint telemetry dogs. Fig. 4 shows a load dependent mechanical and timing measure derived from a ventricular pressure signal. For comparison, data for placebo controls (sterile water, CTRL) combined volume / time are shown.

Control (oral) treatment: Quantitatively, the hemodynamic and mechanical status of individual dogs at the start of the experiment (ie at baseline) is considered to be within the normal physiological range for this species. Were in good agreement with previously reported values (eg, Table 1). In dogs given a 4-day oral vehicle (control value), the mean heart rate (HR) before dosing, mean systolic pressure (MSP), and peak systolic left ventricular pressure change rate (ie dP / Dt _max ) values were (respectively) 108 ± 7 bpm, 132 ± 1 mmHg, and 2,464 ± 86 mmHg / s. Similarly, mean left ventricular end-diastolic (full) pressure (EDP: 12 ± 2 mmHg) was consistent with normal cardiac function.

The value is an estimated value of mean ± standard error of mean, left ventricular pressure signal (LVP). Data is the average of pre-dose averages collected over 4/5 (CTRL / IVA) and / or 11/12 (IVA / CTRL) test days.
+: SET: systolic ejection time; CT: systolic time; FT: full time; RT: relaxation time; S / D: systolic to diastolic ratio (SET / RT + FT); n / u: no unit.
^* : By paired two-sided student t-test (SigmaPlot 12.3; SysStat Software, Inc.).

Table 2A shows acute veins of either vehicle (VEH, sterile water) or omecamtibmecarbyl (OM) in awake telemetry beagle dogs in a repeated placebo therapy setting (CTRL, sterile water for at least 5 days). Left ventricular end-diastolic pressure (EDP) and mean systolic pressure (MSP) and peak rate of change of each of diastolic / systolic (dP / dt _min , dP / dt) measured before and during internal administration _max ).

Values are either pre-dose (average for at least 25 minutes before) and / or during (D1-D4, 5) in either vehicle (VEH, n = 7) or omecamtivecalvir (OM, n = 7) Mean ± standard error of the mean for ensemble averages taken at The relative (%) variation from the pre-dose value is italicized. OM treatment was administered for 30 minutes over 30 minutes over a 3-hour period according to two dose escalation designs targeting plasma concentrations of 600 and 1000 ng / mL for a cumulative dose of 5.293 mg / kg (D1 And D3) followed by a 60 minute maintenance infusion (D2 and D4). Media treatment was time and volume matched.

Table 2B shows vehicle (VEH, sterilized water) or omecamtiv mecarvir (OM) in awake telemetry beagle dogs in a repeated ivabradine therapy setting (IVA, 5 mg / kg twice daily for at least 5 days). Left ventricular end-diastolic pressure (EDP) and mean systolic pressure (MSP) and the respective peak rate of change in diastolic / systolic (dP / measured) measured before and during any acute intravenous administration of dt _min , dP / dt _max ).

Values are either pre-dose (average for at least 25 minutes before) and / or during (D1-D4, 5) in either vehicle (VEH, n = 7) or omecamtivecalvir (OM, n = 7) Mean ± standard error of the mean for ensemble averages taken at The relative (%) variation from the pre-dose value is italicized. OM treatment was administered for 30 minutes over 30 minutes over a 3-hour period according to two dose escalation designs targeting plasma concentrations of 600 and 1000 ng / mL for a cumulative dose of 5.293 mg / kg (D1 And D3) followed by a 60 minute maintenance infusion (D2 and D4). Media treatment was time and volume matched.

Table 3A shows acute veins of either vehicle (VEH, sterile water) or omecamtive mecarbyl (OM) in awake telemetry beagle dogs in a repeated placebo therapy setting (CTRL, at least 5 days with sterile water). was measured prior to the inner administration and during the show was obtained / estimated from the left ventricular pressure, the estimated maximum speed of the cardiac muscle contraction element shortening (V _max) and left ventricular dilatation time constant (Tau).

Values are either pre-dose (average for at least 25 minutes before) and / or during (D1-D4, 5) in either vehicle (VEH, n = 7) or omecamtivecalvir (OM, n = 7) Mean ± standard error of the mean for ensemble averages taken at The relative (%) variation from the pre-dose value is italicized. OM treatment was administered for 30 minutes over 30 minutes over a 3-hour period according to two dose escalation designs targeting plasma concentrations of 600 and 1000 ng / mL for a cumulative dose of 5.293 mg / kg (D1 And D3) followed by a 60 minute maintenance infusion (D2 and D4). Media treatment was time and volume matched.

Table 3B shows the acute intravenous of either vehicle (VEH, sterile water) or omecamibmecarvir (OM) in a repeated ivabradine therapy setting (IVA, 5 mg / kg twice daily for at least 5 days). was measured before and during its administration, shown is obtained / estimated from the left ventricular pressure, the estimated maximum speed of the cardiac muscle contraction element shortening (V _max) and left ventricular dilatation time constant (Tau).

Values are either pre-dose (average for at least 25 minutes before) and / or during (D1-D4, 5) in either vehicle (VEH, n = 7) or omecamtivecalvir (OM, n = 7) Mean ± standard error of the mean for ensemble averages taken at The relative (%) variation from the pre-dose value is italicized. OM treatment was administered for 30 minutes over 30 minutes over a 3-hour period according to two dose escalation designs targeting plasma concentrations of 600 and 1000 ng / mL for a cumulative dose of 5.293 mg / kg (D1 And D3) followed by a 60 minute maintenance infusion (D2 and D4). Media treatment was time and volume matched.

  Table 4A shows acute veins of either vehicle (VEH, sterile water) or omecamibmecarvir (OM) in awake telemetry beagle dogs in a repeated placebo therapy setting (CTRL, sterile water for at least 5 days). The duration of left ventricular systolic mechanical ejection (SET), contraction (CT), fullness (FT), and relaxation (RT), estimated from the left ventricular pressure waveform before and during internal administration, As well as the systolic to diastolic mechanical cardiac cycle duration ratio (S / D).

Values are either pre-dose (average for at least 25 minutes before) and / or during (D1-D4, 5) in either vehicle (VEH, n = 7) or omecamtivecalvir (OM, n = 7) Mean ± standard error of the mean for ensemble averages taken at The relative (%) variation from the pre-dose value is italicized. OM treatment was administered for 30 minutes over 30 minutes over a 3-hour period according to two dose escalation designs targeting plasma concentrations of 600 and 1000 ng / mL for a cumulative dose of 5.293 mg / kg (D1 And D3) followed by a 60 minute maintenance infusion (D2 and D4). Media treatment was time and volume matched.

  Table 4B shows vehicle (VEH, sterilized water) or omecamtive mecarbyl (OM) in awake telemetry beagle dogs in a repeated ivabradine therapy setting (IVA, 5 mg / kg twice daily for at least 5 days). Left ventricular systolic mechanical ejection (SET), contraction (CT), fullness (FT), and relaxation (estimated from the left ventricular pressure waveform before and during any acute intravenous administration of RT) duration as well as systolic to diastolic mechanical cardiac cycle duration ratio (S / D).

Values are either pre-dose (average for at least 25 minutes before) and / or during (D1-D4, 5) in either vehicle (VEH, n = 7) or omecamtivecalvir (OM, n = 7) Mean ± standard error of the mean for ensemble averages taken at The relative (%) variation from the pre-dose value is italicized. OM treatment was administered for 30 minutes over 30 minutes over a 3-hour period according to two dose escalation designs targeting plasma concentrations of 600 and 1000 ng / mL for a cumulative dose of 5.293 mg / kg (D1 And D3) followed by a 60 minute maintenance infusion (D2 and D4). Media treatment was time and volume matched.

Ivabradine (oral) treatment alone: In conscious beagle dogs, repeated oral administration of IVA significantly reduced heart rate (HR: -24 ± 3%, P <0.05) and increased left ventricular filling time (FT : + 81 ± 13%, P <0.05), effective reduction of mechanical systolic to diastolic duration ratio (S / D: −35 ± 3%, P <0.05), improved filling / Suggested increase. In fact, the end-diastolic filling pressure (EDP: + 40 ± 12%, P <0.05) and dP / dt _max , i.e., the preload-dependent inotropic index (+ 8 ± 3%, P <0.05) Increased with IVA therapy (Table 1). These temporal and mechanical changes are consistent with the known pharmacology of ivabradine.

Omecamtivecalvir (intravenous) treatment alone: acute OM administration (intravenous) in awake beagle dogs caused a dose-dependent extension of systolic ejection time and diastolic time constant, while mechanical systolic versus diastole Increasing the period duration ratio resulted in negligible changes in the mechanical index (Figure 1). For example, at dose levels expected to produce a stable plasma concentration of 600 ng / mL (ie, D2), systolic ejection time increases by + 37 ± 6% (vs. + 6 ± 2% for VEH) The systolic to diastolic ratio was increased by + 59 ± 21% (vs. −8 ± 4% for VEH), while dP / dt _max was only −1 ± 4% (vs. −1 ± 3 for VEH) %) Change. At the highest dose level assayed (D4, target plasma concentration of 1000 ng / mL), OM has significant cardiac promotion (+ 65 ± 20% vs. −8 ± 6% for VEH) and rapid dependence-dependent inotropic index Caused a decrease (eg, V _max : −19 ± 8 vs. −2 ± 3% for VEH), suggesting acute dysfunction (eg, S / D: + 216 ±, possibly as a result of impaired filling / relaxation). 52, -3 ± 8% for VEH, and tau: + 72 ± 16, + 8 ± 5% for VEH).

Combination of ivabradine (oral) and omecamtibmecarbyl (intravenous) treatment: The overall effects of OM (eg, increased systolic / relaxation time) appear to be widely maintained in the IVA therapy setting. It was broken. For example, at dose levels expected to produce a stable plasma concentration of 600 ng / mL (ie, D2), systolic ejection increased by + 46 ± 4% (vs. + 6 ± 2% for VEH) and mechanical The systolic to diastolic ratio was prolonged by + 48 ± 5% (vs. 0 ± 4% for VEH). However, at the highest OM dose level, concomitant IVA administration only blunted the OM-induced systolic to diastolic duration ratio (+ 111 ± 19 vs. + 216 ± 52% for OM alone) Rather, induced cardiac promotion (+ 10 ± 10 vs. + 65 ± 20% for OM alone) and rapid functional decline observed at the highest OM dose level (eg, V _max : −4 ± 4) OM alone appeared to override both -19 ± 8%).

  Considering that IVA did not suppress OM-induced changes in relaxation (tau: + 72 ± 8 vs. + 72 ± 16% with OM alone), these effects are related to negative chronotropic effects mediated by IVA It appears to be due to an extension of the ventricular filling time.

  Other uses of the disclosed method will be apparent to those skilled in the art based on, among other things, a review of this patent document.

Claims (36)

  A method of treating a subject with heart failure, comprising administering to the subject a myocardial myosin activator and a sinoatrial node If current inhibitor.   2. The method of claim 1, wherein the myocardial myosin activator is omecamtivemecarbyl, or a pharmaceutically acceptable salt or hydrate thereof.   The method according to claim 1 or 2, wherein the sinoatrial node If current inhibitor is ivabradine, or a pharmaceutically acceptable salt or hydrate thereof.   4. The method of claim 3, wherein the omecamibmecarbyl or a pharmaceutically acceptable salt or hydrate thereof and ivabradine or a pharmaceutically acceptable salt or hydrate thereof are administered sequentially. .   5. The administration of the omecamibmecarbyl or a pharmaceutically acceptable salt or hydrate thereof is prior to the administration of the ivabradine or a pharmaceutically acceptable salt or hydrate thereof. the method of.   5. The administration of the omecamibmecarbyl or a pharmaceutically acceptable salt or hydrate thereof is after the administration of the ivabradine or a pharmaceutically acceptable salt or hydrate thereof. the method of.   4. The method of claim 3, wherein the omecamibmecarbyl, or a pharmaceutically acceptable salt or hydrate thereof, and ivabradine or a pharmaceutically acceptable salt or hydrate thereof are administered simultaneously. .   8. The method of claim 7, wherein the omecamibmecarbyl or a pharmaceutically acceptable salt or hydrate thereof and ivabradine or a pharmaceutically acceptable salt or hydrate thereof are formulated simultaneously.   The omecamibmecarbyl or a pharmaceutically acceptable salt or hydrate thereof, ivabradine or a pharmaceutically acceptable salt or hydrate thereof, or both, orally, intravenously, subcutaneously, intramuscularly, 9. The method according to any one of claims 3 to 8, wherein the method is administered intrathecally or via inhalation.   10. The method according to any one of claims 2 to 9, wherein the omecamtivmecarbyl or a pharmaceutically acceptable salt or hydrate thereof is administered orally.   10. The method according to any one of claims 3 to 9, wherein the ivabradine or a pharmaceutically acceptable salt or hydrate thereof is administered orally.   The method according to any one of claims 2 to 11, wherein the omecamibmecarbyl or a pharmaceutically acceptable salt or hydrate thereof is administered in a total daily dose of 10 mg to 200 mg.   13. The method of claim 12, wherein the omecamibmecarbyl or a pharmaceutically acceptable salt or hydrate thereof is administered in a total daily dose of 12.5 mg to 75 mg.   14. The method according to any one of claims 3 to 13, wherein the ivabradine or a pharmaceutically acceptable salt or hydrate thereof is administered in a total daily dose of 2.5 mg to 20 mg.   15. The method of any one of claims 1-14, wherein the subject is suffering from congestive heart failure.   16. The method of any one of claims 1-15, wherein the subject is suffering from systolic heart failure.   17. The method according to any one of claims 1 to 16, wherein the subject is suffering from heart failure with reduced left ventricular ejection fraction.   Administration of the omecamtibmecarbyl or a pharmaceutically acceptable salt or hydrate thereof, and ivabradine or a pharmaceutically acceptable salt or hydrate thereof is compared with administration of omecamtibmecarbyl alone. 18. A method according to any one of claims 3 to 17, which results in a reduction in ischemic events.   Administration of the omecamtibmecarbyl or a pharmaceutically acceptable salt or hydrate thereof, and ivabradine or a pharmaceutically acceptable salt or hydrate thereof is compared with administration of omecamtibmecarbyl alone. 19. The method of any one of claims 3-18, wherein the method results in a decrease in the systolic to diastolic ratio.   Administration of the omecamtibmecarbyl or a pharmaceutically acceptable salt or hydrate thereof, and ivabradine or a pharmaceutically acceptable salt or hydrate thereof is compared with administration of omecamtibmecarbyl alone. The method according to any one of claims 3 to 19, which results in a decrease in troponin levels.   Administration of the omecamibmecarbyl or a pharmaceutically acceptable salt or hydrate thereof, and ivabradine or a pharmaceutically acceptable salt or hydrate thereof compared to administration of ivabradine alone. 19. A method according to any one of claims 3 to 18 which results in an improvement in sex.   A pharmaceutical composition comprising a myocardial myosin activator and a sinoatrial node If current inhibitor.   23. The composition of claim 22, wherein the sinoatrial node If current inhibitor is ivabradine, or a pharmaceutically acceptable salt or hydrate thereof.   24. The composition of claim 23, wherein the ivabradine is present as ivabradine hydrochloride.   25. The composition according to any one of claims 22 to 24, wherein the myocardial myosin activator is omecamcibmecarbyl, or a pharmaceutically acceptable salt or hydrate thereof.   26. The composition of claim 25, wherein the omecamtivemecarbyl is present as omecamtivemecarbyl dihydrochloride hydrate.   27. A composition according to any one of claims 22 to 26 in the form of a tablet.   28. The composition of claim 27, further comprising a controlled release agent; a pH modifier; a filler; and a lubricant.   30. The composition of claim 28, wherein the controlled release agent comprises methylcellulose, hydroxypropyl methylcellulose, or a combination thereof.   30. The composition of claim 28 or 29, wherein the pH modifier comprises fumaric acid.   31. A composition according to any one of claims 28 to 30, wherein the filler comprises microcrystalline cellulose, lactose monohydrate, or a combination thereof.   32. A composition according to any one of claims 28 to 31 wherein the lubricant comprises magnesium stearate.   Omecamtibmecarbyl or a pharmaceutically acceptable salt or hydrate thereof for use in combination with ivabradine or a pharmaceutically acceptable salt or hydrate thereof for the treatment of heart failure.   Ivabradine or a pharmaceutically acceptable salt or hydrate thereof for use in combination with omecamtivemecarbyl or a pharmaceutically acceptable salt or hydrate thereof for the treatment of heart failure.   Combination therapy for oral administration comprising ivabradine, or a pharmaceutically acceptable salt or hydrate thereof, and omecamtibmecarbyl, or a pharmaceutically acceptable salt or hydrate thereof, as independent entities medicine.   36. Use of a combination therapeutic according to claim 35 in the treatment of the heart failure.